Studies of the neuropathological alterations seen in Alzheimer's Disease (AD) and the molecular and cellular changes underlying them have yielded a wealth of information regarding the etiology of this devastating disease. The combined studies outlined in Projects 1-3 will extend upon this existing knowledge with rigorous cell biological, molecular, biochemical, behavioral, and electrophysiological studies of neuronal cells in vitro and in several mouse models of AD. These studies have the potential to provide greater insight into the etiology of AD as well as to elucidate possible novel targets for AD therapy. The Scientific Core will be a center devoted to facilitating the experiments proposed in Projects 1-3 that require the use of primary neuronal and organotypic cultures, genetically modified animals, immunological reagents, and yeast- reconstituted y-secretase. The existence of this centralized facility will ensure that the experiments outlined in Projects 1-3 will be completed in the most timely and cost-effective manner. Many of the studies proposed in this Program Project Grant will require the use of high-quality neuronal cultures to validate initial findings from transformed cell lines. In Specific Aim I, the Core will be responsible for performing the routine tasks involved in the preparation of primary neuronal and organotypic cultures needed by Projects 1-3. As all of the findings of Projects 1-3 will ultimately be validated and tested in intact animals, the experiments outlined in these Projects will also require the breeding and maintenance of genetically modified animals. Thus the breeding and maintenance of transgenic mice is Specific Aim II of the Core. In order to aid in the characterization of new protein-protein interactions, protein localization, and protein phosphorylation, the Scientific Core will be a keysource of new polyclonal antibodies, including phosphorylation state- specific antibodies, as described in Specific Aim III. Finally, the reconstitution of y-secretaseactivity in the simple eukaryote P. pastoris for genetic manipulation and screening is Specific Aim IV.